Kidney stones (nephrolithiasis) is a common disorder in the United States. Kidney stones can be of different compostion and each type can result from a wide variety of causes. A great number of these underlying causes are either not yet identified or we do not know how the underlying condition leads to nephrolitiasis. The long-term objective of this work is to understand the pathophysiology of nephroliathisis and to provide a database to improve diagnosis and treatment of kidney stones. The aim of the current proposal is to address five specific areas of the pathophysiology of nephrolithiasis using a combination of human, animal and basic science approaches. (1) A common cause of calcium stones is a hereditary condition called absorptive hypercalciuria. This Program has defined a gene associated with this condition. In the proposal, the molecular mechanism of how this disease gene leads to kidney stones will be defined. (2). In a subset of patients, uric acid stones may be linked to defects in insulin action in the kidney. This proposal seeks to prove that insulin resistance can cause kidney stones. (3) One complication of popular weight reduction diets with high protein contents is calcium nephrololithiasis. The calcium stone is caused by high calcium and low citrate levels in the urine (citrate normally protects against calcium stones). This proposal will work out how these high protein diets lead to the urine abnormalities and put the subjects at risk for calcium stones. (4) While women have a lower incidence of kidney stones than men throughout life, kidney stones suddenly become quite frequent at the time of menopause. There are several reasons for this change including the calcium from bone loss passively being excreted in the urine. An additional mechanism is direct calcium leaking into the urine from the kidney due to estrogen lack. This proposal will define the mechanism of this primary renal calcium leak. (5) There has been a lot of publicity and controversy regarding whether dietary calcium restriction, a previously accepted therapy, is actually protective or may even be harmful for patients with calcium nephrolithiasis. Some of the disparate results and hence controversy stem from varying degrees of calcium interacting with another substance oxalate in the intestine and urine. This proposal will address the nature of calcium-oxalate interaction and how it impacts on the risk of developing kidney stones.